Disinfectant and anti-inflammatory composition and method of using same



United States Patent DISINFECTANT ANll) AZNTl-INFLAMMATORY gEMPOSITIONAND METHOD OF USING Comparison shows that 6-chlono-1,2-benzisothiazolonehas equivalent or superior activity against most germs of arepresentative selection, while its oral toxicity is roughly four timesless than that of the previously known com- "ice Rudolf Fischer,Sandbuhl, Kehrsatz, near Bern, Switzer- 5 pound. Besides possessingthese advantages over S-chloland, assignor to Dr. A. Wander, S.A., Bern,Switzerro-1,2-benzisothiazolone as an intestinal disinfectant, 6- land,a Swiss :P chloro-l,Z-benzisothiazolone is eminently suited as an N y qFflefl F 1962, 233,152 agent for combating inflammations of the skin andmu- Claims priority, applicagitgnlss/vggzerland, Mar. 24, 1960, cousmembrane and as a wound disinfectant, for example 3 Claims. (Cl. 10 inthe form of ointment, dusting powder and spray.

The novel 6-chloro-1,2-benzisothiazolone, which is suit- Thi i acontinuationqmpart to my copending liable as an antiseptic,anti-inflammatory agent and especi- Cation Serial 117 243 fil d March 221961 now ally as an oral intestinal disinfectant, is represented byabandoned, U16 fOllOWlI'lg FOl'ITlUlB. I!

This invention relates generally to compositions of matter for use inhuman and veterinary medicine, and

. 4 /3 more particularly to a pharmaceutical composition suit- 5 able asan intestinal and wound disinfectant and anti-in- 2N1I flammatory agentwhich comprises 6-chloro-l,2-benzisothiazolone as the active compound.It relates also to a 20 S (I) method of preventing or combatingintestinal and wound I infections and inflammations of the skin andmucous The P l of 6'chl'oroLZ'bGHZSOthIFIZOIOM may membrane by oral orlocal administration of 6-chloro-l, be carried 91115 111 a y wn per seby either Z-benzisothiazolone in a suitable pharmaceutical form. (a)reactmg a compound of the garland Formula II:

Certain derivatives of benzisothiazolone are known to exert agrowth-inhibiting or lethal action against a wide 0-2 spectrum ofmicroorganisms like bacteria, fungi and protozoa. A fairly large numberof such compounds were 01 investigated by us for their suitability asantiseptics and SZ as intestinal disinfectants. As regards thegrowth-inhibiting action the following regular features were found: inwhich Z denotes a group capable of reacting with a by- (1) An intenseand broad action appears only on sub drogen atom linked to the nitrogenatom of ammonia,

stitution of benzisothiazolone in the positions 2, 5 or with ammonia, or

6; substituents in 4- or 7-position however diminish the (b) condensingto ring closure through cleavage of HZ efiect. a compound according toFormula II, in which one of the (2) Monosubstituted products exert thebest effect; a two Z radicals is replaced by an amino group, or

second substituent reduces the action. (c) treating4,4-dichloro-2,2'-dithiosalicylic acid di- Of the benzisothiazolonesmonosubstituted in 2-, 5- or amide with a diluted aqueous base.

6-position, the previously known 5-chloro-l,2-benziso- The synthesis of6 chloro 1,2 benzisothiazolone is thiazolone and the new6-chloro-1,2-benzisothiazolone 40 preferably carried out by reacting acompound according showed the broadest range of action (microbiologicspecto Formula II, in which Z denotes a halogen atom like trum) coupledwith the greatest intensity of effect, the bromine or chlorine, withammonia in the presence of bactericidal or bacteriostatic properties of6-chlorol,2- an inert solvent like carbon tetrachloride or chloroformbenzisothiazolone being considerably superior to those of and of ahydrogen halide-binding agent. The reaction the S-isomer against variousgerms. On the other hand, can also be carried out in the heterogeneousphase, for 6-chloro-1,Z-benzisothiazolone orally is roughly 4 timesexample by treating the solution of a compound accordless toxic than5-chloro-1,2-benzisothiazolone and thus ing to Formula II in an organicsolvent with aqueous possesses a decisive advantage over the latter asan inammonia solution or 'by introducing gaseous ammonia testinaldisinfectant. These properties of the 6-chloro-1, into the former. As ahydrogen halide-binding agent,

Z-benzisothiazolone in comparison with the previously ammonia itself,which must then be used in three times known S-isomer are morespecifically shown by the figthe equivalent quantity, or a basic solventlike pyridine ures given in the following table. In this table, theaction can be employed.

on various microorganisms is expressed in terms of the Where one of theZ radicals in Formula II is an amino limit concentration of the activesubstance in gm. per group, warming is generally sufiicient to bringabout ml., which still inhibits growth of said microorganisms. ringclosure. In this case the other Z radical is prefera- The oral toxicitytests were performed on mice using bly a chlorine atom. A startingmaterial according to alkaline solutions of the test substances. FormulaII in which Z denotes a chlorine atom is ob- Action Oral toxicity Limitconcentration (gm./ml.) for- Toler- Compound LDao, ated Max. mg./ dose,LD, Staphy- Esche- Psen- Tricho- Tricho- Tricho- Monilia Aspen Triehokg.ii1g./ 1ng./ lococcus riseliia domonas phyton phyton phyton albicansgillus monas kg. kg.

aui'eus coli pyocyanea radians rubruin sclionleini niger fetus6-cl1loro-1,2-benzisothiazolone 1/150, 000 1/40, 000 1/10, 000 1/200,000 1/200, 000 1/200, 000 1/60, 000 1/1, 000 1/10, 000 1,400 1, 0002,150

i i i ia zb i g iffi 1/50, 000 1/10, 000 1/10, 000 1/20, 000 1/20, 0001/100, 000 1/50, 000 1/1, 000 1/10, 000 390 215 681 tained, for example,by treating acid chloride disulphide of Formula III:

(III) with chlorine. If, prior to treatment with chlorine, this acidchloride disulphide is reacted with ammonia, there is obtained 2 chloromercapto 4 chlor-o-benzoic acid amide, which can also be used as astarting material.

Example I A solution of 20 gm. of2-chloromercapto-4-chlorobenzoylchloride in 150 ml. of carbontetrachloride is added to 150 ml. of a vigorously stirred and cooled 25%aqueous solution of ammonia. The mixture is allowed to react for 30minutes at room temperature, 2 N sodium hydroxide solution is then addeduntil dissolution takes place, the carbon tetrachloride layer is removedand acidification is carried out. The precipitated product is drawn offby suction, washed with water and precipitated from diluted sodiumhydroxide solution with diluted hydrochloric acid. There are obtained 11gm. of white 6-chloro-1,2-benzisothiazolone with the melting point 270to 272 C.

ExampleZ gm. of 4,4-dichloro-2,2'-dithiosalicylic acid diamide arestirred at 50 C. in 50 ml. of 2 N sodium hydroxide solution untildissolution occurs. The solution is allowed to cool and 25 ml. ofsaturated sodium chloride solution are added. The precipitated sodiumsalt of 6-chloro-1,2- benzisothiazolone is drawn off by suction, washedwith brine, dissolved in about 100 ml. of water and precipitated with anexcess of 2 N hydrochloric acid. There are obtained 6.5 gm. of6-chloro-1,2-benzisothiazolone with the melting point 270 to 272 C.

Example 3 18.6 gm. of 4,4-dichloro-2,2'-dithiosalicylic acid diamide aresuspended in 100 ml. of carbon tetrachloride and, while stirring, asolution of 8 gm. of bromine in 50 ml. of carbon tetrachloride is addeddrop by drop. After 30 minutes the orange product is drawn off bysuction, suspended in 100 ml. of glacial acetic acid and boiled untildissolution occurs. 500 ml. of water are added, the solution is cooledand the product is drawn off by suction. There are obtained 13.5 gm. of6-chloro- 1,2-benzisothiazolone of melting point 269 to 271 C.

If the 2 'bromomercapto 4 chloro benzoic acid amide obtained above isallowed to lie exposed to the air, ring closure likewise occurs withhydrogen bromide being split off. By warming gently the process ofconversion can be ended even during the course of 2 to 3 hours.

Example 4 9.9 gm. of Unguentum hydrophilicum USP 16 and 0.1 gm. of6-ch1oro-1,2-benzisothiazolone are reduced to a fine powder and mixed.There is obtained an ointment for external application, which has anexcellent therapeutic effect, for example, in pyoderma, dermatomycosis,ulcers and the like.

4 Example 5 By mixing intimately 9.85 gm. of talcum and 0.15 gm. of6-chloro-1,2-benzisothiazolone in finely pulverized form there isobtained a powder for external application, e.g., for the treatment ofwounds.

If in this powder lactose is substituted for talcum there is obtained adisinfectant powder for surgical use.

Example 6 150 mg. of 6-chloro-1,Z-benzisothiazolone are dissolved in amixture of 4 ml. of isopropyl alcohol, 0.2 ml. of acetone and 2 ml. ofhexylene glycol. As a propellant gm. of freon are added and the liquidis introduced into a spray bottle. The spray is used for thedisinfection of wounds.

Example 7 200 gm. of 6-chloro-1,2-benzisothiazolone and gm. of aluminiumhydroxide are mixed in a finely pulverized state and granulated in thepresence of a little water and sodium alginate. The dried granulate iscompressed, in the presence of 75 gm. of maize powder as well as 75 gm.of talcum and a small quantity of magnesium stearate, into tabletsweighing 500 mg. each. These tablets are used for intestinaldisinfection, excellent results being obtained in adults with 1 to 2tablets a day.

I claim:

1. A method of preventing and combating inflamations of the skin andmucous membranes and Wound infections of a living animal which comprisesapplying 6-chloro-1,2- benzis-othiazolone locally to a living animal ina pharmaceutically acceptable form.

2. A method of preventing and combating intestinal infections of aliving animal which comprises administering6-chloro-1,2-benzisothiazolone orally to a living animal in non-toxicpharmaceutically acceptable dosage form.

3. A pharmaceutical composition which comprises a therapeutically usefulamount of 6-chloro-1,2-benzisothiazolone as an essential activeingredient having disinfectant and anti-inflammatory action admixed witha physiologically acceptable pharmaceutical carrier.

References Cited by the Examiner UNITED STATES PATENTS 2,767,174 10/1956Katz et al 260304 2,870,015 1/1959 Allen et al. 260--304 3,065,12311/1962 Hinton 162-161 OTHER REFERENCES Katz: Chem. Abst., vol; 49, col.3161, 1955.

McClelland et al.: Chem. Abst., vol. 42, p. 908, 1948.

Zinsser: Textbook of Bacteriology, 7th ed., 1934, Appleton, Century Co.,New York, N.Y., p. 303.

Schwartz: Surface Active Agents, 1949, Interscience Publishers, Inc.,New York, N.Y., pp. 116 and 117.

JULIAN S. LEVITT, Primary Examiner.

MORRIS O. WOLK, LEWIS GOTTS, Examiners.

P. SABATINE, S. ROSEN, Assistant Examiners.

1. A METHOD OF PREVENTING AND COMBATING INFLAMMATIONS OF THE SKIN ANDMUCUOUS MEMBRANES AND WOUND INFECTIONS OF A LIVING ANIMAL WHICHCOMPRISES APPLYING 6-CHLORO-1,2BENZISOTHIAZOLONE LOCALLY TO A LIVINGANIMAL IN A PHARMACEUTICALLY ACCEPTABLE FORM.